Hyaluronic acid is a naturally occurring biopolymer exerting numerous biological activities in bacteria and more complex animal organisms, including man. Naturally occurring hyaluronic acid may be found in highly evolved animal tissues, mostly present in intercellular spaces. It may be found in practically every part of living organisms, its distribution being almost ubiquitous in tissues and in organ parenchyma, reaching greater concentration in lax connective tissue and specifically in vitreous humour and joint synovial fluid. The serum levels of hyaluronic acid are generally between 10 and 100 μg/L. The lung content of the different forms of hyaluronic acid varies between 15 and 170 μg/gr of dry weight. Lung hyaluronic acid is primarily found in perialveolar and peribronchial tissue. It is drained through the lymphatic system and finally broken down in hepatic lymph nodes. Up to a short time ago, hyaluronic acid was traditionally derived from natural deposits such as cockscomb, or bovine connective tissue by separation methods consisting of an enzyme digestion, a specific separation intended to remove the proteins and a purification to obtain the crude extract. These methods present several disadvantages connected to high production costs, poor control over molecular weight, and risk of viral infection.
Hyaluronic acid may also be produced by means of bio-fermentation. Biotechnological processes such as Gram-positive bacterial fermentation have recently been used: this technique allows the formation of potentially unlimited resources of hyaluronic acid biopolymers devoid of the aforementioned drawbacks. A mucous capsule of hyaluronic acid envelops Streptococci (Gram-positive bacteria). Hyaluronic acid produced by streptococcal fermentation varies in molecular weight from 1 to 4 MDa.
Hyaluronic acid is a member of the glycosaminoglycan family, composed of linear, non-ramified, disaccharide polyanionic chains wherein disaccharide units, composed of n-acetylglucosamine and glucuronic acid, bonded each other by glucoside links, are repeat structures. Hyaluronic acid molecular weight may vary from hundreds of thousands to millions of Daltons. Unlike other glycosaminoglycans, hyaluronic acid contains no sulphate groups, is free from covalent bonds with proteins, and is thought to possess, amongst all mucopolysaccharide substances, the simplest chemical structure.
In body tissues, hyaluronic acid is found bound to cell membranes, joined to other macromolecules, or as a free polysaccharide. It is unique in its ability to bond and retain large amounts of water in the interfibrillar spaces—up to 6 liters of water per gram of hyaluronic acid—thus forming the backbone of the amorphous colloidal matrix acting as cement between cells and connective fibers. As a result of its influence on interstitial volume, water conductivity and macromolecule diffusion, hyaluronic acid plays a significant effect in regulating microcirculatory exchanges.
Within the skin, solutions of hyaluronic acid in water give rise to gels that act as dampers. Hyaluronic acid plays an important role in the body, both for its mechanical and transport properties. It has shown to be important in different tissue functions such as hydration, lubrication, solute transport, cell detachment and migration. Hyaluronic acid also plays a central role in controlling cell growth and differentiation in addition to tissue morphogenesis. Hyaluronic acid solutions are typically viscoelastic and pseudoplastic. The viscoelastic properties of hyaluronic acid, important in its use as a biomaterial, are determined by the concentration and molecular weight of its chains. The molecular weight of the different forms of hyaluronic acid is polydispersed and highly variable, ranging between 10,000 and 10,000.000 Da.
Bronchial asthma is a disease displaying acute reversible bronchoconstriction associated with airway inflammation and hyper-responsiveness leading to excessive bronchospasm in response to a variety of external stimuli that may be specific (allergens), non specific chemicals (histamine, metacholine), or physical agents (ultasound nebulized water, cold air, polluting gases). It is a well known fact that hyaluronic acid is currently used in many fields of medicine: it is employed in different settings such as orthopaedics and surgery. The use of hyaluronic acid in the treatment of diseases of the respiratory tract, specifically involving the lung and bronchi, is described in the International Patent Application WO 95/26735; salt, alcohol, aqueous, or dimethylsulphoxide solutions of hyaluronic acid are administered in the trachea of experimental animals at a daily dose between 10 μg/kg and 2 mg/kg.